PROJECT SUMMARY/ABSTRACT The overall goal of this proposed research is to develop a biomarker that prognosticates and correlates with the clinical expression of pain in sickle cell disease (SCD). Severe, debilitating pain is the most common complication of SCD, an inherited hemoglobinopathy affecting approximately 100,000 people in the United States. Despite the known genetic defect, there is significant variability in pain expression in patients with SCD. Clinically, some patients experience frequent and recurrent pain while others experience pain only occasionally. Currently, there is no plasma biomarker, linked to pain biology, that can prognosticate patients who are likely to experience more pain than other patients. The lack of a prognostic biomarker for pain is a barrier to targeted, personalized pain treatment. SCD is associated with chronic inflammation with elevated inflammatory mediators (e.g. cytokines, chemokines, lipids) at baseline that increase further during acute pain. However, the degree of inflammation is likely highly variable among patients. Multiple factors, including ongoing effects of recurrent vaso-occlusion, ischemia-reperfusion injury, and hemolysis contribute to SCD inflammation and pain. This project is centered on the concept that pain in SCD is heterogeneous and driven by a complex milieu of inflammatory effectors and immune regulators. A prognostic biomarker that quantitatively and comprehensively assesses the combination of these immune effectors and regulators and correlates with pain in SCD will fill a significant gap in SCD pain research. Ideally, such a biomarker could provide prognostic data and define inclusion criteria for pain clinical trials of immunomodulatory drugs. The following aims are proposed for the R61 Phase: 1) Derive the inflammatory index (I.l.com) for pain in patients with SCD by identifying inflammatory and immune regulatory gene probe sets that will optimally distinguish healthy controls, patients with SCD in baseline health, and patients with SCD in acute pain and 2) Determine whether co-expressed gene modules from patients with SCD correlate with clinical pain data and are concordant with genes included in the I.I.com. Subsequently, the following aims are proposed for the R33 Phase: 1) Determine the reliable and clinically meaningful changes of the I.I.com in patients with SCD and 2) Investigate the preliminary clinical validity of the I.I.com as a prognostic biomarker for pain in patients with SCD. Our collaborative and multidisciplinary team brings research expertise in SCD pain biology, inflammation, and SCD patient-reported outcomes. Our proposed work will refine, replicate and validate the I.I.com as a prognostic biomarker for SCD pain.